The Diagnosis and Treatment of Low T3 Syndrome in Neurocritical Patients

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The Diagnosis and Treatment of Low T3 Syndrome in Neurocritical Patients Yihao Chen 
Peking Union Medical College Hospital Jianbo Chang 
Peking Union Medical College Hospital Rui Yin 
Peking Union Medical College Hospital Junxian Wen 
Peking Union Medical College Hospital Baitao Ma 
Peking Union Medical College Hospital Wei Zuo 
Peking Union Medical College Hospital Xiao Zhang 
Peking Union Medical College Hospital Junji Wei  ( [email protected] )
Peking Union Medical College Hospital
Research article
Posted Date: December 19th, 2019
DOI: https://doi.org/10.21203/rs.2.19099/v1
License: This work is licensed under a Creative Commons Attribution 4.0 International License.   Read Full License
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Abstract Background
Low serum T3 level is considered as a strong predictor of mortalities and poor prognosis in critical care patients. Few reports, however, focus on neurocritical patients. The application of hormone replacement therapy (HRT) in neurocritical patients with low T3 syndrome also remains controversial. We studied the role of low T3 state as a predictor in neurocritical patients and presented our experience of HRT from a single-center perspective.
Methods
From January 2012 to October 2018, a total of 32 neurocritical patients with low T3 syndrome were admitted to the neuro-intensive care unit (NICU) of Peking Union Medical College Hospital. Among them, 18 (56.25%) patients received HRT (HRT group) since the diagnosis of low T3 syndrome, while the other 14 (43.75%) patients did not (non-HRT group). We collected the clinical baseline and laboratory data of all the patients and conducted follow-up from 3 to 72 months. Overall survival was assessed by the Kaplan-Meier curve and compared by the log-rank test. Univariate and multivariate regression analysis was applied to estimate the prognostic power of HRT for mortality. We also performed the Mann-Whitney U test or t-test to assess the inuence of HRT on the nal neurological function.
Results
The cohort consists of 32 patients, with an average Glasgow Coma Scale (GCS) of 6.41 (HRT=6.44±3.14, non-HRT=6.36±2.06). The neurocritical events include postoperative complications (n=18), traumatic brain injury (n=8), and spontaneous intracerebral hemorrhage (n=6). A total of 15 (46.87%) deaths were recorded (HRT=7, non-HRT=8). In the HRT group, the low T3 situation in 5 patients (33.3%) was corrected and 10 (66.7%) were not. It turns out that the overall survival rate of the non-HRT group was signicantly lower than that of the HRT group (P=0.034, 16.445 vs. 47.470 months). The non-HRT group has 3.322 times the mortality risk of the HRT group, according to univariate regression analysis, while the multivariate regression analysis showed no signicant difference in mortality risk between the two groups (P=0.087, HR=0.340 95%CI 0.099-1.172). There was no signicant difference in the short and long-term effects of HRT on neurological function (short-term GCS P=0.587, long-term GCS P=0.419, long- term GOS P=0.419).
Conclusion
Low T3 syndrome can signicantly inuence the prognosis of neurocritical patients. Therefore much attention should be paid to the changes in serum T3 level during treatment. Although it is unclear to what extent can HRT improve the short or long-term outcome of neurological function, it can signicantly benet the survival of neurocritical patients.
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1 Introduction Low T3 syndrome has been described in the critical patients but without a prior history of thyroid disease. The most common manifestations include low triiodothyronine (T3) level, average or low thyroid- stimulating hormone (TSH) level and increased reverse triiodothyronine (rT3) level.
Many studies have shown that a low T3 level was an independent predictor of poor prognosis in neurocritical patients1 − 3, and low T3 syndrome can inuence various systems. For example, some studies found a rapid fall in serum T3 and T4 levels within 15 to 30 minutes after the initiation of cardiac bypass surgery and that change could last for days4. There is a strong positive correlation between low serum T3 and poor prognosis in patients with end-stage renal diseases5. Similarly, low T3 level is also a valid predictor of disease outcome in patients in intensive care units3, 6. Patients with severe neurological diseases often have more complications and higher mortality rates, for which low T3 state is also an important prognostic indicator, as supported by plenty of evidence. Lieberman et al. found that the thyroid function of 87% of individuals with severe traumatic brain injury fell below the mid-normal value7. Many reports also showed that low T3 syndrome is one of the indicators of poor prognosis for cerebral infarction patients1, 8. Their ndings indicated the participation of central hypothyroidism in the most critical patients and it might be related to disturbance of thyroid hormone metabolism. Low T3 syndrome is common in patients with brain tumors and is positively correlated with shorter survival of glioma patients9. Despite the above, whether the thyroid hormone abnormalities are a physiological adaptation or a pathological change, is still debated10, 11. Whether these changes are pathologic or physiologic and whether hormone replacement therapy (HRT) can benet such patients, require further research. Here we aim to summarize the clinical features and outcomes of neurocritical patients with a low T3 level.
2 Methods
2.1 Patient Population and Setting A retrospective review was performed on the medical records of patients admitted to the neurosurgery department of Peking Union Medical College Hospital between January 2012 and October 2018. We collected data from 1201 patients with triiodothyronine lower than the ordinary level and eliminated those with primary thyroid diseases. Totally 32 neurocritical patients with low T3 levels were included in the cohort, among which 18 received HRT and 14 did not. The HRT received contains a daily dose of 100 ug of oral levothyroxine sodium tablet starting right after the diagnosis of low T3 states (treatment course: 18 days, median range: 5.75-30 days, 25-75th percentile). All patients were followed up through phone consultation for 3 months to 6 years. Table 1 summarizes the diagnosis and comorbidities of patients. The cohort was 50% male (median age = 46, 38–54 years, 25-75th percentile) and 50% female (median age = 56, 46.7–74 years, 25-75th percentile). In terms of neurocritical events, 18 cases of postoperative complications including intracranial hemorrhage (n = 3), subarachnoid hemorrhage (n = 2), cerebral infarction (n = 4), acute hydrocephalus (n = 3), central nervous system infection (n = 4) and severe cerebral
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edema (n = 5), were recorded, and eight cases of severe traumatic brain injury as well as six spontaneous intracerebral hemorrhage were diagnosed. During the progression of diseases, infection of the central nervous system (n = 14), pulmonary infection (n = 22) and heart failure (n = 8) also emerged.
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Clinical diagnoses of patients Number of patients
Cerebral Operation related complication*
Urinary tract infection 4
Acute kidney injury 5
One patient can have more than one diagnosis, so the sum exceeds the absolute number of patients. *18 cases of postoperative complications include intracranial hemorrhage (n = 3), subarachnoid hemorrhage (n = 2), cerebral infarction (n = 4), acute hydrocephalus (n = 3), central nervous system infection (n = 4) and severe cerebral edema (n = 5). End-stage of death cases are often combined with multiple organ dysfunction.
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Endocrine  
Chronic myeloid leukemia 1
One patient can have more than one diagnosis, so the sum exceeds the absolute number of patients. *18 cases of postoperative complications include intracranial hemorrhage (n = 3), subarachnoid hemorrhage (n = 2), cerebral infarction (n = 4), acute hydrocephalus (n = 3), central nervous system infection (n = 4) and severe cerebral edema (n = 5). End-stage of death cases are often combined with multiple organ dysfunction.
2.2 Data Collection Data of all the patients with low T3 syndrome, which were adequately followed up, were analyzed. We recorded demographic information (name, gender, age, etc.), primary or secondary neurocritical events and their complications, and past disease history (e.g., cardiovascular diseases and infectious diseases). Total cortisol level test, liver function test, renal function test, complete blood cell analysis, coagulation function test and myocardial enzyme test were conducted using fasting blood samples to help evaluate the condition and progression of disease. We only took data from critical conditions into account if multiple test results exist. GCS at different stages were obtained from the medical records. Glasgow Outcome Scale (GOS) and the last GCS were obtained from follow-up.
2.3 Laboratory Measurements All tests were conducted in the same laboratory using standard methods. The laboratory department of Peking Union Medical College Hospital has established its reference range. Serum fT3 (normal range: 1.80–4.10 pg/ml), T3 (normal range: 0.66–1.92 ng/ml), fT4 (normal range: 0.81–1.89 ng/dl), T4 (normal range: 4.30–12.50 ug/dl) and TSH (normal range: 0.38–4.34 µlU/ml) levels were measured by enzyme- linked immunosorbent assay (ELISA) from samples collected under critical conditions.
2.4 Statistical Analysis Data analysis was performed using IBM SPSS 24.0 Statistical Software (SPSS Inc., Chicago, IL, United States). The Kolmogorov-Smirnov test was used to determine the distribution of continuous variables. For data of a non-normal distribution, results were presented as median and range and were compared using the Mann-Whitney U test. For normally distributed data, results were reported as mean ± SD and were compared by t-test. Survival curves of HRT were calculated by the Kaplan-Meier method and differences in survival were estimated using the log-rank test. The differences were considered to be statistically signicant when P < 0.05. We also performed a Cox proportional hazards model, determined relative risks for mortality using univariate and multivariate Cox regression analysis, and presented as
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hazard ratio (HR; 95% Cl). Covariates tested in the Cox model were gender, age, BMI, fT3, GCS and HRT. Variables were included in the multivariate analysis if they had a P-value < 0.05 in the univariate analysis or if the factors were regarded as clinically important confounders. When two-tailed P < 0.05, the results were considered to be statistically signicant.
3 Results
3.1 Patients and Management A total of 16,830 patients attended the neurosurgery department of Peking Union Medical College Hospital and completed the thyroid function test during January 2012 and October 2019. Out of the 16,830 patients, 1201 (7.13%) of them had lower-than-normal free triiodothyronine levels. Among them, we excluded 343 (28.56%) outpatients and another 826 (68.77%) patients were also excluded due to the absence of neurocritical events during hospitalization. Eventually, we admitted 32 (2.67%) patients into the cohort of this study and none of them had primary thyroid diseases or were taking medications that could affect thyroid hormones. The median age of all the subjects was 53 years (range 41.25-64, 25-75th percentile) and the cohort was 50% male and 50% female. All patients had a GCS no more than 11 during neurocritical events. The top 3 neurocritical events are postoperative complications (3 intracranial hemorrhage, 2 subarachnoid hemorrhages, 4 cerebral infarction, 3 acute hydrocephalus, 4 central nervous system infection and 5 severe cerebral edema), traumatic brain injury (n = 8), and spontaneous intracerebral hemorrhage (n = 6) (Fig. 1). Of the patients, 68.75% had pulmonary disease (22 cases of pulmonary infection, 1 pulmonary embolism and 4 respiratory failure) and 34.37% had cardiovascular disease (8 cases of heart failure, 5 malignant arrhythmias and 11 hypertension). We summarized the diagnosis information in Table 1.
3.2 Lab Test Findings and Outcomes The baseline data and lab ndings are as shown in Table 2. The HRT group had a median age of 46 years and that of the non-HRT group is 54 years. There was no signicant statistical difference between the age of both groups (P = 0.059), nor between gender (P = 0.164) and between BMI (P = 0.319). All the subjects had average free triiodothyronine (fT3), free thyroxine (fT4), T3, T4, and TSH of 1.38 pg/ml, 0.94 ng/ml, 0.411 ng/ml, 4.58 µg/dl, and 0.47 µlU/ml, respectively. Twenty-two (52%) patients had lower-than-normal fT4 levels, and 14 (33.3%) patients had a normal TSH level. The non-HRT group had a higher median total cortisol concentration (9.75 µg/dl) than the HRT group (4.66 µg/dl), but with no statistical difference (P = 0.253). All 32 patients presented a median GCS at 6 (HRT = 5.5, non- HRT = 6) with no statistical difference between two groups either (P = 0.722). The mean GCS reached 8.50 ± 0.73 (HRT = 8.17 ± 1.07, non-HRT = 8.93 ± 0.98, P = 0.587) when they were discharged. In the follow- up period, the mean GCS of all patients was 8.56 ± 0.97 (HRT = 9.33 ± 1.28, non-HRT = 7.57 ± 1.49, P = 0.419). 14 (43.8%) patients encountered infection of central nervous system (HRT = 10 or 55.55%, non- HRT = 4 or 28.57%). There was a total of 15 (46.9%, HRT = 7 or 38.88%, non-HRT = 8 or 57.14%) death in our study.
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HRT (n = 18)
Non-HRT (n = 14)
Male sex (%) 50(n = 16) 38.8(n = 7) 64.28(n = 9)
BMI (kg/m2) 24.20 ± 0.59 24.72 ± 0.74 23.53 ± 0.76
Thyroid hormones      
Laboratory ndings      
Blood sugar (mmol/l) 9.95 ± 0.79 10.18 ± 1.11 9.66 ± 1.16
Albumin(g/l) 30.69 ± 0.88 31.39 ± 1.37 29.79 ± 0.97
Hemoglobin(g/l) 90.75 ± 3.27 92.61 ± 4.18 88.36 ± 5.32
White blood cell(× 109)* 15.86(12.93–20.54) 17.66(13.09–21.32) 13.71(10.10-17.36)
Fibrinogen(g/l) 3.98 ± 0.36 3.51 ± 0.48 4.59 ± 0.53
Clinical ndings      
GCS at discharge 8.50 ± 0.73 8.17 ± 1.07 8.93 ± 0.98
GCS (follow-up) 8.56 ± 0.97 9.33 ± 1.28 7.57 ± 1.49
GOS (follow-up) 2.75 ± 0.31 3.00 ± 0.41 2.43 ± 0.47
CNS infection (%) 43.8(n = 14) 55.55(n = 10) 28.57(n = 4)
Survival outcome(death%) 46.9(n = 15) 38.88(n = 7) 57.14(n = 8)
*For data following non-normal distribution, results were expressed as median and range (median, 25–75th percentile). For data following a normal distribution, results were expressed as mean ± SD.
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3.3 Thyroid Function after Oral Administration of Levothyroxine Sodium Before receiving HRT (100 µg oral levothyroxine sodium daily), all patients were in accordance with typical low T3 syndrome manifestation, with serum fT3 levels lower than normal range. Fifteen patients in the HRT group were re-tested for thyroid function after treatment. The median time of the second test was 9 days (8–15 days, 25-75th percentile) after oral administration of levothyroxine sodium. Five (33.3%) of them regained normal fT3 level (mean = 2.29 ± 0.12) while the other 10 (66.7%) still has an abnormally low level of fT3 (mean = 1.39 ± 0.08). We compared the second results of fT3 (1.69 ± 0.51), fT4 (1.00 ± 0.29) and TSH (1.14 ± 2.96) from HRT group with baseline data (1.41 ± 0.06, 1.15 ± 0.34, and 1.13 ± 0.62, respectively) using paired-samples t-test and found no statistical difference between them (P = 0.146, P = 0.671, P = 0.978).
3.4 Effects of Hormone Replacement Therapy
3.4.1 Survival Prognostic Relevance of Low T3 Eighteen patients (HRT group) received oral administration of levothyroxine sodium (100 µg per day, treatment course median is 18 days, range 5.75-30 days, 25-75th percentile). All 32 patients were followed up for 3 to 72 months. We compared the median overall survival of patients in the HRT group (n = 18) with that of the non-HRT group (n = 14). Kaplan-Meier method and Cox regression survival analysis were used to calculate the mortality rate at 72 months of follow-up. The median survival of the HRT group was 47.470 months, which is signicantly longer than that of the non-HRT group (median 16.445 months, P = 0.034). Figure 2 shows the Kaplan-Meier curves. In univariate regression analysis, HRT still made statistical differences, where the non-HRT group had 3.322 times the mortality risk of the HRT group (P = 0.043, HR = 0.301, 95%Cl, 0.094–0.964), shown as Fig. 3. Though the multivariate analysis, which includes age and GCS, indicated no statistical difference between the mortality risk of both groups, the hazard ratio (0.340) between both groups can still be considered as a signicant inuencer of prognosis (Fig. 4).
3.4.2 Neurological Prognostic Relevance of Low T3 We compared the GCS at discharge and GCS and GOS at the last follow-up session between the HRT group (n = 18) and the non-HRT group (n = 14). The mean GCS score of the HRT patients at discharge was 8.17 ± 1.07 and the non-HRT ones recorded 8.93 ± 0.98. The t-test showed there was no signicant statistical difference in short-term neurological outcomes between the two groups (P = 0.615). The mean GCS score at the last follow-up of the HRT patients was 9.33 ± 1.28 and the non-HRT was 7.57 ± 1.49. There was still no statistical difference between the two groups (P = 0.419). The mean GOS at the last follow-up of the two groups was 3.00 ± 0.41 and 2.43 ± 0.47, with no statistical difference, conrmed by t- test. (Fig. 5)
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4 Discussion Reichlin and Protnay et al. had found that the thyroid hormone levels dropped in some critical patients without thyroid diseases back in the 1970s. Then, in 1982, Leonard Wartofsky and Bunnan from Washington Hospital proposed the concept of low T3 syndrome12. The low T3 syndrome is a disorder in thyroid hormone metabolism under various stress states, most commonly with the reduction in triiodothyronine as early as 24 hours after onset13. The primary mechanism behind the change is the inhibition of 5'-deiodinase. Usually, the free T4 level is among the normal range but could slightly exceed the limits. We observed a decline in T3 in our cohort at an average of 10 days after neurocritical events, and half of the subjects showed normal T4 levels. 5'-deiodinase activation induces the conversion of T4 into serum reverse triiodothyronine (rT3), which usually elevates in non-thyroid disease. However, many studies conrmed that the increase of rT3 could not accurately distinguish non-thyroid disease from hypothyroidism14.
The low T3 state was regarded as an independent predictor of mortalities in critical patients, especially for critical events and heart failure caused by any incidences15. Low T3 level, cardiac risk factors and mortality are strictly related16. The abnormal thyroid hormone levels were in companion with the failure of other systems or organs. According to a study on hormones in patients with end-stage renal disease undergoing hemodialysis, 44.3% of all 167 subjects had low T3 syndrome, which is also associated with mortalities of 6 months and 12 months (P = 0.007)5. The liver is involved in the conversion of tetraiodothyronine (T4) into triiodothyronine (T3), and patients with liver cirrhosis often had thyroid hormone abnormalities. A study demonstrated that nearly 67% of liver cirrhosis patients in intensive care units (ICU) had low T3 syndrome, and fT3 and fT4 levels may be used as predictors of mortality in such critical patients17. Wehmann et al. found that the incidence of low T3 syndrome in hematological malignancies was 54%18. Wawrzyskaet al. tested thyroid hormone concentration in severe respiratory failure patients in ICU and found that low T3 syndrome seems to be related to the decrease of PO2. Dying patients can have the lowest total T3 level, while the increase of TT3 serum concentration closely correlates with the improvement of the clinical state of patients12. Low fT3 levels have been interpreted as a physiological response aimed to reduce energy expenditure and minimize protein catabolism. Therefore, low T3 syndrome can be usually found in patients with malnutrition, fasting, and energy restrictions. A survival analysis of 669 hemodialysis patients with low T3 syndrome showed that nutritional status might serve as a “bridge” between low T3 levels and mortality. They also reported that age, cholesterol, and serum albumin concentration could be related to the extent of T3 level decline in different patients19. Therefore, low fT3 levels might also be an indicator of disease progression.
Neuroendocrine dysfunction (NED) is widespread in neurocritical patients. It has been reported that at least one NED was found in 35–50% of individuals with severe traumatic brain injury7, 20, 21, and this may be related to the disorder of the hypothalamic-pituitary-target organ axis during acute progression. Stress is a defensive mechanism of the body…